Gastric Reflux Resistant Dosage Forms

ABSTRACT

Gastric resistant film-forming compositions are described herein. The composition comprises a gastric resistant natural polymer, a film-forming natural polymer, and optionally a gelling agent. Suitable gastric resistant natural polymers include polysaccharides such as pectin and pectin-like polymers. The film-forming composition can be used to prepare soft or hard shell gelatin capsules which can encapsulate a liquid or semi-solid fill material or a solid tablet (Softlet®) comprising an active agent and one or more pharmaceutically acceptable excipients. Alternatively, the composition can be administered as a liquid with an active agent dissolved or dispersed in the composition. The compositions are not only gastric resistant but may also prevent gastric reflux associated with odor causing liquids, such as fish oil or garlic oil, encapsulated in a unit dosage form and esophageal irritation due to the reflux of irritant drugs delivered orally.

FIELD OF THE INVENTION

The invention is in the field of gastric resistant dosage forms.

BACKGROUND OF THE INVENTION

The use and manufacture of enteric dosage forms are well known in theart. Such dosage forms are described in Remington's PharmaceuticalSciences, 18^(th) Ed., Mack Publishing Co., Easton, Pa. (1990). Entericdosage forms are useful for protecting the contents of the dosage formfrom the gastric conditions of the stomach and/or to protect gastrictissue from an irritant material contained in the dosage form. Entericdosage forms can also be useful in preventing gastric reflux due to thepresence of odor-causing liquids, such as fish oil or garlic oil, in thedosage form.

Enteric-coated dosage forms are typically produced by a film coatingprocess, where a thin film layer of an acid-insoluble (enteric) polymeris applied to the surface of a pre-manufactured dosage form, such as atablet, and to a lesser extent hard and soft capsules. The entericcoating method involves spraying an aqueous or organic solution orsuspension of one or more enteric polymers onto tumbling or movingtablets or capsules, followed by drying at elevated temperatures.Enteric dosage forms made by this coating method can suffer from variousprocess-related problems that affect the performance and/or appearanceof the coating. For example, “orange peel” surface formation, also knownas surface roughness or mottling, may result. More seriously, coatintegrity failure may occur, such as cracking or flaking off of theenteric polymer coating. All coating processes present inherentproblems, including possible uneven distribution of the coatingingredients, which can occur under multivariate coating processes.

These problems are common to all enteric dosage forms. However, theproblems faced during the coating of gelatin or polysaccharide capsulesare even more critical due to the delicate and heat sensitive nature ofthe soft elastic capsule shell. Both hard and soft capsules can undergothermally induced agglomeration and distortion of the capsule shell.Moreover, the smoothness and elasticity of the capsule surface makes itdifficult to form an intact adhering enteric coating, without asubcoating step to improve the surface of the capsule for coating.Finally, the enteric coatings cause the loss of the normally shiny andclear appearance of gelatin capsule shells, which is a major reason forthe popularity and acceptance of gelatin capsules.

Attempts to overcome the limitations associated with coated dosage formshave been made. For example, WO 2004/03068 by Banner Pharmacaps, Inc.(“the '068 application”) describes a gel mass that is useful inmanufacturing enteric soft or hard shell capsules or enteric tabletswithout the need for a coating. The gel mass comprises a film-forming,water-soluble polymer, an acid-insoluble polymer and optionally, one ormore excipients such as plasticizers, colorants and flavorants. The '068application, however, discloses the use of synthetic acid-insolublepolymers such as cellulosic polymers and acrylic acid-methacrylic acidcopolymers (Eudragit®) which are present in a concentration from 8 to20% by weight of the wet gel mass.

U.S. Patent Application Publication No. 2003/0175335 by Scott et al.(“the '335 application”) describes film forming compositions containingpectin, at least one film-forming polymer, and a setting system forpreparing soft and hard shell capsules. The concentration of pectin is 5to 60% by weight, preferably 10 to 40% by weight. The concentration ofthe film-forming polymer is 40 to 95% by weight, preferably 50 to 85% byweight. The '335 application discloses a film containing 5 to 25%,preferably 10 to 20% by weight pectin which is suitable to prepare hardshell capsules with enteric properties.

There exists a need for a gastric resistant film-forming compositionthat contains a gastric resistant natural polymer at relatively lowerconcentrations.

Therefore, it is an object of the invention to provide a gastricresistant film-forming composition comprising a gastric resistantfilm-forming composition which comprises a gastric resistant naturalpolymer at relatively low concentrations and methods of manufacturingthereof.

It is further an object of the invention to provide a gastric resistantcapsule shell, which can encapsulate a liquid, semi-solid, or solidfill, which contains a gastric resistant natural polymer at relativelylow concentrations and methods of manufacturing thereof.

BRIEF SUMMARY OF THE INVENTION

Gastric resistant film-forming compositions comprise a gastric resistantnatural polymer, a film-forming natural polymer, and optionally agelling agent. The composition can be used for drug delivery either as aliquid or as a gelled capsule. Suitable gastric resistant naturalpolymers include polysaccharides such as pectin and pectin-likepolymers. The concentration of the gastric resistant natural polymer isless than about 5% by weight of the composition, preferably from about 2to about 4% by weight of the composition. Suitable film-forming naturalpolymers include gelatin and gelatin-like polymers. The concentration ofthe film-forming natural polymer is from about 20 to about 40% by weightof the composition, preferably from about 25 to about 40% by weight ofthe composition. Suitable gelling agents include divalent cations suchas Ca²⁺ and Mg²⁺. The concentration of the optional gelling agents isless than about 2% by weight of the composition, preferably less thanabout 1% by weight of the composition. The composition can furthercomprise one or more plasticizers to facilitate the film-formingprocess.

The film-forming composition can be used to prepare soft or hard shellgelatin capsules which can encapsulate a liquid or semi-solid fillmaterial or a solid tablet (Softlet®) comprising an active agent and oneor more pharmaceutically acceptable excipients. Alternatively, thecomposition can be administered as a liquid with an active agentdissolved or dispersed in the composition. The compositions are not onlygastric resistant but may also prevent gastric reflux associated withodor causing liquids, such as fish oil or garlic oil, encapsulated in aunit dosage form as well as esophageal irritation due to the reflux ofirritant drugs delivered orally.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

“Gastric resistant natural polymer” as used herein refers to refers tonatural polymers or mixtures of natural polymers which are insoluble inthe acidic pH of the stomach.

“Film-forming natural polymer” as used here refers to polymers usefulfor surface coatings that are applied by spraying, brushing, or variousindustrial processes, which undergo film formation. In mostfilm-formation processes, a liquid coating of relatively low viscosityis applied to a solid substrate and is cured to a solid,high-molecular-weight, polymer-based adherent film possessing theproperties desired by the user. For most common applications, this filmhas a thickness ranging from 0.5 to 500 micrometers (0.0005 to 0.5millimeters, or 0.00002 to 0.02 inches).

“Gelling agent” as used herein refers to substances that undergo a highdegree of cross-linking or association when hydrated and dispersed inthe dispersing medium, or when dissolved in the dispersing medium. Thiscross-linking or association of the dispersed phase alters the viscosityof the dispersing medium. The movement of the dispersing medium isrestricted by the dispersed phase, and the viscosity is increased.

II. Composition

Gastric resistant film-forming compositions comprising (1) a gastricresistant natural polymer; (2) a film-forming natural polymer; andoptionally (3) a gelling agent, are described herein.

A. Gastric Resistant Natural Polymers

Exemplary gastric resistant natural polymers include pectin andpectin-like polymers which typically consist mainly of galacturonic acidand galacturonic acid methyl ester units forming linear polysaccharidechains. Typically these polysaccharides are rich in galacturonic acid,rhamnose, arabinose and galactose, for example the polygalacturonans,rhamnogalacturonans and some arabinans, galactans and arabinogalactans.These are normally classified according to the degree of esterification.In high (methyl)ester (“HM”) pectin, a relatively high portion of thecarboxyl groups occur as methyl esters, and the remaining carboxylicacid groups in the form of the free acid or as its ammonium, potassium,calcium or sodium salts;

useful properties may vary with the degree of esterification and withthe degree of polymerization. Pectin in which less than 50% of thecarboxyl acid units occur as the methyl ester is normally referred to aslow (methyl)ester or LM-pectin. In general, low ester pectin is obtainedfrom high ester pectin by a treatment at mild acidic or alkalineconditions. Amidated pectin is obtained from high ester pectin whenammonia is used in the alkaline deesterification process. In this typeof pectin some of the remaining carboxylic acid groups have beentransformed into the acid amide. The useful properties of amidatedpectin may vary with the proportion of ester and amide units and withthe degree of polymerization.

In one embodiment, the gastric resistant natural polymer is pectin. Thegastric resistant natural polymer is present in an amount less thanabout 5% by weight of the composition, preferably from about 2 to about4% by weight of the composition.

B. Film-Forming Natural Polymers

Exemplary film-forming natural polymers include gelatin and gelatin-likepolymers. In a preferred embodiment, the film-forming natural polymer isgelatin. A number of other gelatin-like polymers are availablecommercially. The film-forming natural polymer is present in an amountfrom about 20 to about 40% by weigh of the composition, preferably fromabout 25 to about 40% by weight of the composition.

C. Gelling Agent

The composition can optionally contain a gelling agent. Exemplarygelling agents include divalent cations such as Ca²⁺ and Mg²⁺. Source ofthese ions include inorganic calcium and magnesium salts and calciumgelatin. The gelling agent is present in an amount less than about 2% byweight of the composition, preferably less than about 1% by weight ofthe composition.

D. Plasticizers

One or more plasticizers can be added to the composition to facilitatethe film-forming process. Suitable plasticizers include glycerin,sorbitol, sorbitans, maltitol, glycerol, polyethylene glycol,polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters,triethyl citrate and combinations thereof. The concentration of the oneor more plasticizers is from about 8% to about 30% by weight of thecomposition. In one embodiment, the plasticizer is glycerin and/orsorbitol.

III. Method of Making

The film-forming composition can be used to prepare soft or hard shellgelatin capsules which can encapsulate a liquid or semi-solid fillmaterial or a solid tablet (Softlet®) comprising an active agent and oneor more pharmaceutically acceptable excipients. Alternatively, thecomposition can be administered as a liquid with an active agentdissolved or dispersed in the composition.

A. Capsules

1. Shell

The film-forming composition can be used to prepare soft or hardcapsules using techniques well known in the art. For example, softcapsules are typically produced using a rotary die encapsulationprocess. Fill formulations are fed into the encapsulation machine bygravity.

The capsule shell can comprise one or more plasticizers selected fromthe group consisting of glycerin, sorbitol, sorbitans, maltitol,glycerol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms,citric acid, citric acid esters, triethyl citrate and combinationsthereof.

In addition to the plasticizer(s), the capsule shell can include othersuitable shell additives such as opacifiers, colorants, humectants,preservatives, flavorings, and buffering salts and acids.

Opacifiers are used to opacify the capsule shell when the encapsulatedactive agents are light sensitive. Suitable opacifiers include titaniumdioxide, zinc oxide, calcium carbonate and combinations thereof.

Colorants can be used to for marketing and productidentification/differentiation purposes. Suitable colorants includesynthetic and natural dyes and combinations thereof.

Humectants can be used to suppress the water activity of the softgel.Suitable humectants include glycerin and sorbitol, which are oftencomponents of the plasticizer composition. Due to the low water activityof dried, properly stored softgels, the greatest risk frommicroorganisms comes from molds and yeasts. For this reason,preservatives can be incorporated into the capsule shell. Suitablepreservatives include alkyl esters of p-hydroxy benzoic acid such asmethyl, ethyl, propyl, butyl and heptyl (collectively known as“parabens”) or combinations thereof.

Flavorings can be used to mask unpleasant odors and tastes of fillformulations. Suitable flavorings include synthetic and naturalflavorings. The use of flavorings can be problematic due to the presenceof aldehydes which can cross-link gelatin. As a result, buffering saltsand acids can be used in conjunction with flavorings that containaldehydes in order to inhibit cross-linking of the gelatin.

2. Fill Material

Agents

Soft capsules can used to deliver a wide variety of pharmaceuticallyactive agents. Suitable agents include analgesics, anti-inflammatoryagents, antihelmintics, anti-arrhythmic agents, anti-bacterial agents,anti-viral agents, anti-hypertensive agents, anti-coagulants,anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents,anti-gout agents, anti-malarials, anti-migraine agents, anti-muscarinicagents, anti-neoplastic agents, erectile dysfunction improvement agents,immunosupressants, anti-protozoal agents, anti-thyroid agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, -blockers,cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonianagents, gastro-intestinal agents, histamine H₁ and H₂ receptorantagonists, keratolytics, lipid regulating agents, anti-anginal agents,nutritional agents, opioid analgesics, sex hormones, stimulants, musclerelaxants, anti-osteoporosis agents, anti-obesity agents, cognitionenhancers, anti-urinary incontinence agents, nutritional oils,anti-benign prostate hypertrophy agents, essential fatty acids, nonessential fatty acids, vitamins, minerals and mixtures thereof.

Excipients

Fill formulations may be prepared using a pharmaceutically acceptablecarrier composed of materials that are considered safe and effective andmay be administered to an individual without causing undesirablebiological side effects or unwanted interactions. The carrier is allcomponents present in the pharmaceutical formulation other than theactive ingredient or ingredients. As generally used herein “carrier”includes, but is not limited to surfactants, humectants, plasticizers,crystallization inhibitors, wetting agents, bulk filling agents,solubilizers, bioavailability enhancers, pH adjusting agents, andcombinations thereof.

B. Solutions and Suspensions

Alternatively, the composition can be administered as a liquid with anactive agent dissolved (e.g. solution) or dispersed (e.g. suspension) inthe composition. Suitable active agents are described above. Thesolution or suspension may be prepared using one or morepharmaceutically acceptable excipients. Suitable excipients include, butare not limited to, surfactants, humectants, plasticizers,crystallization inhibitors, wetting agents, bulk filling agents,solubilizers, bioavailability enhancers, pH adjusting agents, flavorantsand combinations thereof.

EXAMPLES Example 1 Gastric Resistant Dosage Form

The composition of the gastric resistant dosage form is shown below.

Component % by weight of the Composition Pectin 4.04 Water 70.78 Calciumchloride (CaCl₂) 0.05 Gelatin (150 bloom bovine bone) 17.70 Glycerin7.43

Example 2 Gastric Resistant Dosage Form

The composition of the gastric resistant dosage form is shown below.

Component % by weight of the composition Pectin 4.04 Water 70.78 Calciumchloride (CaCl₂) 0.05 Gelatin (175 bloom pig skin) 17.70 Glycerin 7.43

Example 3 Gastric Resistant Dosage Form

The composition of the gastric resistant dosage form is shown below.

Component % by weight of the composition Pectin 4.04 Water 70.71 Calciumchloride (CaCl₂) 0.05 Gelatin (150 bloom bovine bone) 17.73 Glycerin7.43

Example 4 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 4.04 Water 70.71 Calciumchloride (CaCl₂) 0.03 Gelatin (150 bloom bovine bone) 17.75 Glycerin7.43

Example 5 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 4.04 Water 70.71 Calciumchloride (CaCl₂) 0.01 Gelatin (150 bloom bovine bone) 17.77 Glycerin7.43

Example 6 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 4.04 Water 70.71 Calciumchloride (CaCl₂) 0.007 Gelatin (150 bloom bovine bone) 17.77 Glycerin7.43

Example 7 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 4.04 Water 68.99 Calciumchloride (CaCl₂) 0.013 Gelatin (150 bloom bovine bone) 17.79 Glycerin9.17

Example 8 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 4.04 Water 61.89 Calciumchloride (CaCl₂) 0.013 Gelatin (150 bloom bovine bone) 22.79 Glycerin11.27

Example 9 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 4.04 Water 54.79 Calciumchloride (CaCl₂) 0.013 Gelatin (150 bloom bovine bone) 27.79 Glycerin13.37

Example 10 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 4.04 Water 47.69 Calciumchloride (CaCl₂) 0.013 Gelatin (150 bloom bovine bone) 32.79 Glycerin15.47

Example 11 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 2.42 Water 49.11 Calciumchloride (CaCl₂) 0.004 Gelatin (150 bloom bovine bone) 33.41 Glycerin15.05

Example 12 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 2.42 Water 49.02 Calciumchloride (CaCl₂) 0.008 Gelatin (150 bloom bovine bone) 33.60 Glycerin15.05

Example 13 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 2.42 Water 49.11 Calciumchloride (CaCl₂) 0.016 Gelatin (150 bloom bovine bone) 33.41 Glycerin15.05

Example 14 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 2.42 Water 49.11 Calciumchloride (CaCl₂) 0.031 Gelatin (150 bloom bovine bone) 33.39 Glycerin15.05

Example 15 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 2.50 Water 47.69 Calciumchloride (CaCl₂) 0.0054 Gelatin (150 bloom bovine bone) 34.33 Glycerin15.47

Example 16 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 3.03 Water 49.11 Calciumchloride (CaCl₂) 0.0049 Gelatin (150 bloom bovine bone) 32.81 Glycerin15.05

Example 17 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 3.03 Water 47.68 Calciumchloride (CaCl₂) 0.0065 Gelatin (150 bloom bovine bone) 33.81 Glycerin15.47

Example 18 Gastric Resistant Dosage Form

The composition of the gastric dosage form is shown below.

Component % by weight of the composition Pectin 3.03 Water 49.11 Gelatin(150 bloom bovine bone) 32.81 Glycerin 15.05

Typical fill materials include, but are not limited to, fish oil, garlicoil, soybean oil, and medium chain triglycerides (“MCT”).

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe material for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1-34. (canceled)
 35. An oral gastric resistant soft capsule shell,prepared by a process comprising: A) preparing a mixture comprising (a)pectin in an amount from 2% to less than 5% by weight; (b) gelatin in anamount from 25% to 40% by weight; (c) glycerol in an amount from 8% to30% by weight; (d) a divalent cation in an amount from 1% to 2% byweight; (e) water; B) casting the gel mass into films or ribbons; and C)forming the capsule shell.
 36. The capsule shell of claim 35, whereinthe concentration of pectin is from 2% to 4% by weight.
 37. The capsuleshell of claim 35, wherein the divalent cation is selected from thegroup consisting of calcium salts, magnesium salts, and calcium gelatin.38. The capsule shell of claim 35, wherein the mixture further comprisesone or more excipients selected from the group consisting of opacifiers,colorants, humectants, preservatives, flavorings, buffering salts andacids, and combinations thereof.
 39. The capsule shell of claim 35,wherein the pectin is high (methyl)ester pectin.
 40. The capsule shellof claim 35, wherein the pectin is low (methyl)ester pectin.
 41. Thecapsule shell of claim 35, wherein the pectin is amidated pectin. 42.The capsule shell of claim 35, wherein the gelatin is bovine gelatin.43. The capsule shell of claim 35, wherein the gelatin is porcinegelatin.
 44. An oral gastric resistant soft capsule shell containing afill composition comprising fish oil, wherein the soft capsule shell isprepared by a process comprising: A) preparing a mixture comprising: (a)pectin present in an amount from 2% to less than 5% by weight of thegastric resistant soft capsule shell; (b) gelatin in an amount from 25%to 40% by weight of the gastric resistant soft capsule shell; (c)glycerol in an amount from 8% to 30% by weight of the gastric resistantsoft capsule shell; (d) a divalent cation in an amount from 1% to 2% byweight of the gastric resistant soft capsule shell; (e) water; B)casting the gel mass into films or ribbons; and C) forming the capsuleshell.
 45. The capsule shell of claim 44, wherein the concentration ofpectin is from 2% to 4% by weight.
 46. The capsule shell of claim 44,wherein the divalent cation is selected from the group consisting ofcalcium salts, magnesium salts, and calcium gelatin.
 47. The capsuleshell of claim 44, wherein the mixture further comprises one or moreexcipients selected from the group consisting of opacifiers, colorants,humectants, preservatives, flavorings, buffering salts and acids, andcombinations thereof.
 48. The capsule shell of claim 44, wherein thepectin is high (methyl)ester pectin.
 49. The capsule shell of claim 44,wherein the pectin is low (methyl)ester pectin.
 50. The capsule shell ofclaim 44, wherein the pectin is amidated pectin.
 51. The capsule shellof claim 44, wherein the gelatin is bovine gelatin.
 52. The capsuleshell of claim 44, wherein the gelatin is porcine gelatin.